The 26-week, multicenter, double-blind study, funded by Symbicort's manufacturer, AstraZeneca, included close to 11,700 patients with mild-to-moderate asthma treated for 26 weeks with either the long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) combination or budesonide alone.

In 2009, FDA requested that manufacturers of LABA-containing products in the U.S. conduct safety analyses, following the publication of two large studies -- the Serevent Nationwide Surveillance trial and SMART (Salmeterol Multicenter Asthma Research Trial) -- which appeared to show an increased risk of asthma-related deaths associated with LABA use.

The first of the trials, reported last March, showed no greater risk for serious asthma-related events in patients treated with the GlaxoSmithKline LABA/fluticasone drug Advair Diskus, compared with those treated with fluticasone alone.

Peters said that when results from a third, ongoing, trial are published, a meta-analysis including all three will be performed. "Results from the first two trials suggest that these drugs are effective in the general population of asthma patients," he told MedPage Today.

The new study included patients with persistent asthma who were age 12 or older and taking daily asthma medication. All patients included in the trial had experienced one to four asthma exacerbations in the year prior to joining the study, but patients who had life-threatening asthma events were excluded.

The primary endpoint was the first serious asthma-related event (a composite of adjudicated death, intubation, and hospitalization), as assessed in a time-to-event analysis. Noninferiority of budesonide-formoterol compared with budesonide alone was defined as an upper limit of the 95% confidence interval for the risk of the primary safety endpoint of less than 2.0. The primary efficacy endpoint was the first asthma exacerbation, as assessed in a time-to-event analysis.

Of the 11,693 patients enrolled in the 26-week trial, 5,846 received treatment with budesonide-formoterol and 5,847 were treated with budesonide alone.

The risk of having an asthma exacerbation was 16.5% lower with the combined therapy than with the monotherapy (HR 0.84, 95% CI 0.74-0.94).

While serious adverse event rates were similar with the two therapies, there were two deaths judged to be asthma-related in the LABA/budesonide group and none in the budesonide-monotherapy group. Six total deaths occurred in the combined-therapy group, compared with eight in the budesonide-alone group.

Peters said one death attributed to asthma occurred in a 68-year-old woman who died of cardiopulmonary failure 8 weeks after suffering cardiac arrest for which she required hospitalization and intubation. The other occurred in a 22-year-old woman who died after taking the study medication for 109 days. While suffering from shortness of breath, the woman took three doses of salbutamol, and became cyanotic, lost consciousness, and died.

The researchers noted that the individual postmarketing safety studies were not powered to assess between-group differences in asthma-related deaths.

The newly published study results, "established the noninferiority of budesonide-formoterol to budesonide with regard to the risk of serious asthma-related events in adults and adolescents with moderate-to-severe asthma," the team concluded.

Since patients with a history of serious asthma-related events were excluded from the trial, the findings cannot be extrapolated to these patients, Peters said. This exclusion was a joint decision by the FDA, the study sponsors, and the independent joint oversight committee.

Another potential study limitation cited by the researchers was the high rate of adherence to the prescribed therapy in both treatment groups, attributed to frequent patient contact and built-in alerts communicated through an interactive voice-response system.

The researchers raised the possibility that lesser adherence could increase the risk of serious asthma-related events.

The study was funded by AstraZeneca, and several authors are noted to be employees of the company.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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